Progress in vascular biology over the past decade has established that blood vessel wall cells express inducible functions that govern thrombosis, interactions with leukocytes, vascular tone, and the growth and metabolic program of neighboring cells. Alterations in these highly regulated functions contribute to the development of vascular diseases. This program will conduct interrelated basic and clinical research to address common pathophysiologic questions related to arterial dysfunction. Project 1, Restenosis: a cascade mechanism (P. Libby) will explore novel hypotheses regarding the role of lesional leukocytes as sources of and amplifiers of signals for proliferation and other responses elicited by balloon injury in atherosclerotic rabbits and humans. Project 2, Thrombotic determinants of vascular responses, (J. Loscalzo) will examine the role of fibrin and its degradation products as modulators of vascular cell and leukocyte functions relevant to arterial injury. Project 3, Molecular markers of arterial endothelial dysfunction (M.A. Gimbrone and M. Cybulsky), will use a monoclonal antibody strategy to seek novel activation markers on vascular wall cells to increase basic knowledge and exploit disease-related cell surface structures in diagnosis and targeted therapy. Project 4, Actin regulatory proteins in arterial dysfunction (D.J. Kwiatkowski and T.P. Stossel) will apply expertise in actin regulatory proteins to study the mechanisms of vascular cell motility, a process important in repair of arterial injury. Project 5, Mechanisms of arterial dysfunctions in diabetes mellitus (M.A. Creager) will investigate the basis of impaired vasodilatory responses to endothelium-dependent agonists in the peripheral resistance arteries of diabetic human patients. Project 6, Basis of altered vasoreactivity in diseased arteries, (P. Ganz and A. Selwyn will explore the mechanisms of endothelial dysfunction and abnormal constriction in coronary and pulmonary arteries in intact humans, and develop early and sensitive functional measures of diseases progression and effects of therapies. Over time, basic knowledge in vascular biology to emerge from Projects 1-4 will lead to new clinical approaches in Projects 5 and 6. Thus, the overall program aims to foster development of useful clinical strategies through the union of basic vascular biology with clinical vascular medicine.